Primary small cell undifferentiated (neuroendocrine) carcinoma of the maxillary sinus

Vol. 98 No. 5 November 2004

ORAL AND MAXILLOFACIAL PATHOLOGY

Editor: Alan R. Gould

Primary small cell undifferentiated (neuroendocrine) carcinoma of the maxillary sinus Anastasia F. Georgiou, BDS, MDSc, FRACDS,a D. Murray Walker, MD, FDSRCS, FRCPath, FFOP, FRCPA,b Ann P. Collins, BDS, LDSRCS, MDS, FRACDS (OMS),c Gary J. Morgan, MB, BS, FRACDS, FRACS,d Jennifer A. Shannon, MB, BS (Hons), PhD, FRACP,d and Michael J. Veness, MB, BS, MMed, FRANZCR,d Westmead, New South Wales, Australia UNIVERSITY OF SYDNEY, INSTITUTE OF CLINICAL AND PATHOLOGICAL MEDICAL RESEARCH, WESTMEAD CENTRE FOR ORAL HEALTH, AND WESTMEAD HOSPITAL

Primary small cell undifferentiated (neuroendocrine) carcinomas of the paranasal sinuses are extremely uncommon neoplasms. This tumor was first reported in this site in 1965, and since then there have been only 61 documented cases in the literature. The median age at presentation is 53 years, with no gender predilection. There is no reported association of occurrence of this tumor with either tobacco use or form of occupation, and case outcome is usually poor. We report a case in a 25-year-old man, initially treated as an odontogenic infection and thus delaying institution of appropriate management. Further investigation identified a locally advanced neuroendocrine carcinoma of the left maxilla. Despite radiotherapy and chemotherapy, the patient exhibited rapid tumor dissemination and died. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:572-8)

Primary neuroendocrine carcinoma of the paranasal sinuses is much less common than that arising in the lung. Excluding Merkel cell carcinomas of the skin, small cell undifferentiated (neuroendocrine) carcinomas in the head and neck region primarily arise in the major salivary glands with a predilection for the parotid gland, as well as in the larynx and rarely the sinonasal region and hard palate. Microscopic features of small cell undifferentiated (neuroendocrine) carcinomas arising in the head and neck region are indistinguishable from those of bronchogenic origin. The number of docu-

mented cases of small cell undifferentiated (neuroendocrine) carcinoma presenting in the sinonasal region is too small to permit precise definition of typical clinical features, but the tumor appears to be aggressive with high potential for destructive local recurrence. In comparison to small cell carcinomas of the lung and larynx, distant spread of primaries originating in the sinonasal region appears to be a less frequent occurrence. This case appears to be the first to demonstrate how a primary neuroendocrine carcinoma may clinically resemble, and thus be treated initially as, an odontogenic infection.

a

Staff Specialist, Department of Oral Medical Surgical Sciences, Westmead Centre for Oral Health, Westmead, New South Wales. b Professor, University of Sydney, and Anatomical Pathology, Institute of Clinical and Pathological Medical Research Westmead, New South Wales. c Consultant, Oral and Maxillofacial Surgery, Westmead Centre for Oral Health, Westmead, New South Wales. d Consultant, Head and Neck Cancer Service, Westmead Hospital, Westmead, New South Wales. Received for publication Dec 16, 2002; returned for revision Feb 7, 2003; accepted for publication Apr 9, 2004. 1079-2104/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.tripleo.2004.04.003

572

CASE REPORT A 25-year-old healthy Caucasian man presented with a 2-week history of left facial swelling. There was no history of tobacco smoking, and the patient’s medical history was noncontributory. He consulted his dentist, who commenced root canal treatment of the left maxillary premolars and first molars, as these teeth were suspected of being responsible for the swelling. There was no improvement of his symptoms. He presented to Westmead Hospital, Sydney, Australia, reporting an increase in the facial swelling with left peri-orbital involvement (Fig 1). He reported epistaxis from the left nostril, lacrimation of his left eye, and paresthesia in the distribution of

OOOOE Volume 98, Number 5

Georgiou et al 573

Fig 2. Occipitomental radiograph demonstrating obliteration of the air shadow of the left maxillary sinus and destruction of its lateral and nasal walls.

Fig 1. Left mid-facial swelling.

the ophthalmic and maxillary division of the left trigeminal cranial nerve. Clinically, the patient had an enlarged left superior cervical lymph node measuring 3cm in diameter. Radiographs demonstrated obliteration of the normal air shadow of the left maxillary sinus (Fig 2). Computed tomography (Fig 3 and Fig 4) and magnetic resonance imaging demonstrated a soft tissue mass with invasion through the anterior, medial, and inferior walls of the left maxillary sinus, encroaching upon the left nasal cavity and associated with destruction of the turbinates. Inferiorly, the tumor extended to the left maxillary alveolus and palate. There was direct tumor extension into the left ethmoid air cells. Superiorly, the tumor extended to the floor of the orbit. There was no evidence of intracranial extension. A biopsy of the left maxillary antral lesion was carried out via a Caldwell-Luc approach. Light microscopic examination demonstrated a highly malignant anaplastic tumor with extensive necrosis and hemorrhage (Fig 5). No antral mucosa was present, and origin of the tumor could not be demonstrated histopathologically. Tumor cells were of intermediate size, with finely stippled chromatin, prominent nucleoli, and sparse cytoplasm. Widespread tumor cell necrosis was apparent and mitotic figures were identified (4 per high power field), some of which were morphologically abnormal. Tumor cells were

loosely coherent, with no evidence of intercellular bridges (Fig 6). Perineural invasion and intravascular spread were not observed microscopically. Immunohistochemistry (Table I) confirmed that the cells were epithelial in nature, with positive staining for keratins in a punctuate perinuclear pattern (pankeratin, AE1/AE3, and 5D3). The tumor cells also showed evidence of neuroendocrine markers including synaptophysin (Fig 7), chromogranin, CD56, and neuron-specific enolase. The tumor cells were negative for desmin, smooth muscle actin, myoglobin, CD99, and cytokeratin 20. These findings supported a diagnosis of primary neuroendocrine carcinoma of the left maxillary sinus. Surgical therapy was deemed inappropriate given the rapidly advancing nature of the tumor and the probable morbidity of a resection, which would have encompassed skin, the left orbit, entire left maxilla, and the anterior cranial floor. Furthermore, the tumor extended into the infratemporal fossa. Platinum-based chemotherapy was initiated, but failed to prevent continued tumor progression. A combination of weekly cisplatin and comprehensive radiotherapy was initiated with a total dose of 60 Gy prescribed. Radiotherapy was accelerated for the first 2 weeks and by the third week of radiotherapy tumor regression was noted. By completion of chemoradiotherapy, the tumor was substantially reduced in size. Three and one half months after diagnosis the patient developed spinal metastases and presented with back pain and signs of spinal cord compression. Paraplegia soon developed despite palliative radiotherapy. The patient died 4 months after diagnosis due to widespread dissemination and bone marrow failure.

574 Georgiou et al

OOOOE November 2004

Fig 3. Computed tomography views demonstrating a destructive lesion occupying left maxillary and ethmoid air sinuses and left nasal cavity with loss of medial, anterior and posterior bony walls of antrum.

Fig 5. Light microscopic appearance of the tumor biopsy, showing sheets of tumor cells, necrosis, and hemorrhage (hematoxylin-eosin stain, original magnification 340). Fig 4. Computed tomography views demonstrating a destructive lesion occupying left maxillary and ethmoid air sinuses and left nasal cavity with loss of medial, anterior and posterior bony walls of antrum.

DISCUSSION Primary small cell neuroendocrine carcinomas of the nasal cavity and paranasal sinuses are rare. Squamous cell carcinoma is the most common malignancy in this site, followed by adenocarcinoma. The first case of small cell carcinoma of the sinosal region was documented by Raychowdhuri in 1965,1 who described this tumor in the fronto-ethmoid sinuses on autopsy of a previously

comatose young female who died of frontal lobe abscess and meningitis. Sixty-one patients with this aggressive neoplasm of the sinonasal region have been reported both in small cases series1-9 and in isolated case reports.9-15 (Table II summarizes those with sufficient clinical data available.) In a retrospective study of extrapulmonary small cell carcinoma, 7 of the 81 tumors identified during a 20-year time period involved the sinuses.7 In a recent prospective study, 9 of the 19 tumors were classified as neuroendocrine or mixed tumors involving the paranasal sinuses,8 however no information was given about individual

OOOOE Volume 98, Number 5

Georgiou et al 575

Table I. Summary of immunohistochemical investigations and other stains of the tumor Positive Immunohistochemistry Keratins Pankeratin (Biogenex) AE1/AE3 (ID Lab Inc) 5D3 (Novocastra Lab Ltd)

Immunohistochemistry Neural Neuron-specific enolase (Neomarkers) CD56 (Neomarkers) Synaptophysin (Zymed Lab Inc) Chromogranin (Biogenex)

Fig 6. Small to intermediate-sized tumor cells with high nuclear to cytoplasmic ratio, finely stippled chromatin, frequent mitoses, and apoptosis (hematoxylin-eosin stain, original magnification 380).

cases to include in our review. Our patient was young in comparison to previously documented cases, with most presenting in the sixth decade (range 26-77 years, median 53 years). There is no gender predilection. Nearly all patients presented with facial pain and epistaxis. Other symptoms described include swelling, nasal obstruction, proptosis, paresthesia, and anosmia. To our knowledge, this is the first case documented that was initially thought to represent an odontogenic infection. Small cell carcinoma of the sinonasal tract has not been reported associated with tobacco use, in contrast to the strong association with the small cell carcinoma in laryngeal, tracheal, and hypopharyngeal sites. No correlation with occupation is described. The histogenesis of small cell carcinoma is not fully defined. Presence of neurosecretory granules and tumor cell affinity for silver stains are features suggestive of neuroendocrine differentiation. Small cell undifferentiated (neuroendocrine) carcinoma of the head and neck has been described as an endocrine tumor of the amine precursor uptake and decarboxylation (APUD) system of Pearse.16 This histogenetic concept is applied to cells of the neuroendocrine system with shared cytochemical and functional properties, such as the argyrophilic Kulchitsky cells. However, such cells have only been rarely described in the nasal cavity and paranasal sinuses. Features common to APUD cells and tumors are dense core cytoplasmic granules, biogenic amine production, and production of neuron-specific enolase or other specific peptides. Cells with APUD characteristics are now most often referred to as neuroendocrine cells.17 Small cell carcinomas may produce ectopic hormones,

Negative Immunohistochemistry S-100 (ID Lab Inc) Desmin (Zymed Lab Inc) Smooth muscle actin (DAKO) Leucocyte common antigen (DAKO) Myoglobin (DAKO) CK20 (Neomarkers) CD99 (Biogenex) Other stains Periodic acid schiff Periodic acid schiff diastase

Fig 7. Positive perinuclear staining with synaptophysin (immunohistochemical stain, original magnification 320).

but clinical manifestations of hormone production are uncommon in these tumors when arising in the head and neck.12 The investigation of ectopic hormone production can be of value in diagnosis and treatment.9 There is 1 reported case of small cell carcinoma of the head and neck associated with a paraneoplastic syndrome resulting from tumor synthesis of antidiuretic hormone.13 It has also been asserted that tumors in the parasinuses and nasal cavity may be of seromucinous origin,2 and that origin of head and neck small cell carcinomas (excluding Merkel cell carcinoma) are explained on the grounds that these tissues share a common foregut origin. Silva et al5 found that the tumor cells were associated with glands in all 20 cases of paranasal neuroendocrine carcinomas evaluated. It was suggested that the glandular epithelium is that of exocrine glands,

OOOOE November 2004

576 Georgiou et al

Table II. Literature review of documented cases of small cell undifferentiated carcinoma: paranasal sinuses and nasal cavity. Modified from Baugh and McClatchey 19869 Author

Age

Sex

Raychowdhuri 19651 Koss et al 19722

65 26 39 42 57 50 56 33 70 54 54

F M F F M M M F M M F

y

z

Kameya et al 19803

Rejowski et al 19824 Silva et al 19825

Location

Treatment

Upper nasal cavity Ethmoid sinus Max sinus Nasal cavity Nasal Cavity Max, ethmoid (R) Max, ethmoid (R), nasal Ethmoid and frontal (R) Maxillary (R) Max, ethmoid, sphenoid Between middle turbinate and septum (L) Precise site of origin could not be ascertained for 14 of the tumors

Remaining 6: 2 middle turbinate 2 middle turbinate and maxillary sinus 2 superior turbinate and ethmoid sinus

Weiss et al 198310 Baugh et al 198612 Soussi et al 199011 Pierce et al 199413 Lo Re et al 199414 Perez-Ordonez et al 19986

Mineta et al 20019 Noguchi et al 200215 Georgiou et al

77 64 60 55 49 59 41 42

F M F M M F F M

38 68 52 55 53 25

F M M M F M

Ethmoid, max sinus (R) Max sinus, nasal Ethmoid (L), frontal Max sinus (L) Ethmoid sinus Max sinus (L) Lateral nasal wall (L) Max sinus (R), ethmoid and nasal cavity Ethmoid sinus (L) Ethmoid sinus (L), nose Ethmoid sinus (L) Max sinus Max sinus Max sinus

Recurrence

None S, RT S S S S, RT S, RT S RT, CTx RT, CTx S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT S, RT RT, CTx RT S S S S S, CTx RT, Ctx RT, CTx RT CTx CTx RT, CTx S S

None None 31 None 35+ 34+ None 31+ None None 31 None None Mets 32 31+ None None None 31 None None 31 35+ 32+ 33 32 Mets None 33+ 32+ None 31+ None Mets Local Local

S, RT, CTx S, RT S, RT, CTx RT, CTx S, RT, CTx RT, CTx

Local + mets Mets Local Mets Mets Local + mets

mets mets mets

mets

mets mets

mets mets mets

Outcome

Survival

DOD DOD NED DOD DOD DUC DOD DOD DOD NED NED NED DUC NED NED DUC DOD NED NED NED NED NED TRD NED DUC DOD NED DOD TRD NED DOD DOD DUC AWD NED DOD AWD AWD

1 mo 16 mo 8 yrs 11 mo 8 mo 10 yrs 6 yrs 2 mo 6 mo 12 mo 12 mo 20 yrs 15 yrs 13 yrs 10 yrs 6 yrs 6 yrs 2 yrs 2 yrs 2 yrs 18 mo 12 mo 2 mo 5 yrs 19 yrs 13 yrs 12 yrs 7 yrs 6 mo 8 mo 27 mo 9 mo MI 16 mo 14.6 mo 21 mo 19 mo 48 mo

DOD AWD AWD DOD DOD DOD

6 24 8 8 17 4

mo mo yrs mo mo mo

Max, maxillary; S, surgery; RT, radiotherapy; CTx, chemotherapy; AWD, alive with disease; DOD, dead of disease; DUC, died of unrealted causes; NED, no evidence of disease; TRD, tumor-related death; MI, myocardial infarction during treatment. *Surgical complication. y Mean 50 years. z 10 male, 10 female. § Died of myocardial infarction during treatment.

which include Bowman’s glands, and that the tumor cells are derived from this epithelium. However, the association of tumor cells with glands is neither universally encountered histopathologically nor consistently reported in the literature.

The nomenclature and classification of neuroendocrine tumors have varied with time, particularly those of the epithelial type. DeLellis18 recently reviewed this controversial area, including a historical perspective and current classifications. Nomenclature has reflected

OOOOE Volume 98, Number 5

concepts of histogenesis, as for example the terms ‘‘APUD tumor’’ or ‘‘APUDoma’’ describe the aminehandling properties of the tumor, while others have favored a functional classification based on tumor hormonal activity while overlooking biological behavior and nomenclature systems based on anatomic location. The term ‘‘carcinoid,’’ introduced by Oberndorfer19 in 1907, has been used by the World Health Organization20 with a classification divided into the categories carcinoid, atypical carcinoid, and small cell carcinoma. There has been much discussion regarding the appropriateness of the term carcinoid, with several points highlighted. The clinician must understand the sense of terminology, as an ‘‘atypical carcinoid’’ is a high-grade neoplasm that merits an aggressive clinical approach relative to the ‘‘typical carcinoid.’’21 In addition, the precise relationship of typical carcinoid tumor to higher grades of neuroendocrine neoplasia is unclear. Mills et al21 suggest a nomenclature scheme reflecting the biology of these lesions and the terminology proposed by Gould et al.22 True or typical carcinoid tumors are designated as such, which aids to separate these from more aggressive neuroendocrine neoplasms. Lesions termed ‘‘atypical carcinoids’’ are considered moderately differentiated neuroendocrine carcinomas, and small cell carcinomas referred to as such, or are termed poorly differentiated neuroendocrine carcinoma, small cell type. Microscopically, small cell undifferentiated (neuroendocrine) carcinomas arising in the head and neck are indistinguishable from those of bronchogenic origin. Typically there are sheets, cords, and ribbons of small cells with little or no cytoplasm, which appear undifferentiated by light microscopy. The nuclei have a uniformly stippled chromatin pattern. Mitotic figures are frequent. Necrosis varies from scattered, individual cell death to irregular zones of infarct-like change. Nuclear molding and encrustation of vessel walls by DNA from degenerating tumors (Azzopardi effect) may be present.21 Intravascular and perineural invasion are common. A fibrovascular stroma is usually present with little or no inflammatory response. Ultrastructurally, nuclei demonstrate condensation of chromatin along the nuclear envelope. Cell junctions are present to a variable degree.21 Membrane-bound cytoplasmic electron dense core granules, 80 to 250 nm in diameter,12 are present. These cannot be differentiated from normal endocrine-type small granules of polypeptide secretion, or from endocrine-type granules in other neuroendocrine tumors. These granules are considered to contain polypeptides and/or biogenic amines.2 Immunohistochemical findings are generally useful in differentiating between small cell tumors of different histogenetic origins. The pattern of immunostaining in

Georgiou et al 577

paranasal small cell undifferentiated (neuroendocrine) carcinoma appears to be similar to that observed in pulmonary small cell carcinoma.6 Typically there is reactivity for cytokeratins, often with a punctuate perinuclear pattern, a feature noted in small cell carcinomas arising in several locations. This pattern corresponds to perinuclear accumulations of intermediate filaments.23 Neuroendocrine markers such as chromogranin, synaptophysin, and neuron-specific enolase are also frequently expressed. Microscopically, the differential diagnosis may include olfactory neuroblastoma and malignant lymphoma. In this case, olfactory neuroblastoma was excluded by negative staining for S100 and the presence of extensive necrosis, which is usually absent or minimal in olfactory neuroblastoma.21 Negative staining with leucocyte common antigen excluded a diagnosis of malignant lymphoma. Small cell undifferentiated (neuroendocrine) carcinoma of the nasal cavity and paranasal sinuses has a propensity for multiple local recurrences, with direct extension into the cranial base and brain. Tumor dissemination is usually a relatively late sequela of head and neck small cell carcinomas, when compared to the behavior of such tumors arising from other anatomic regions. The most frequent sites for distant metastases are the lungs, liver, and bone. Metastasis to osseous sites represented a terminal event in our patient. As small cell carcinoma may metastasize to the head and neck from distant sites, this possibility should be kept in mind when considering a diagnosis of primary small carcinoma. Treatment regimes described include combinations of distinct modalities; surgery alone yields few successes in the treatment of small cell carcinoma of the nasal cavity and paranasal sinuses. Galanis et al7 reported a median time of relapse of 10 months in 5 patients with paranasal tumors treated with surgery alone. Degree of local tumor extension often renders surgery an unsuitable treatment choice, given the probable degree of postoperative morbidity. Small cell undifferentiated (neuroendocrine) carcinoma is radiosensitive, and combinations of surgery and irradiation are likely to achieve the most favorable outcome. Neoadjuvant and concomitant chemotherapy may play a role, particularly since these tumors are considered chemosensitive. Commonly used adjuvant agents include cyclophosphamide, cisplatin, doxorubicin, vincristine, and methotrexate.12 Small cell carcinoma is a highly aggressive neoplasm; extrapulmonary small cell carcinoma is usually a fatal disease with a 13% 5-year survival rate.7 Galanis et al7 reported the median survival of 14 patients with extrapulmonary small cell carcinoma of the head and neck including 7 paranasal cases was 14.5 months. In our review (Table II), the mean survival of 42 patients, where

OOOOE November 2004

578 Georgiou et al information provided, was 21 months. However, recently Fitzek et al8 reported a 74% 5-year survival rate in a prospective study of 19 neuroendocrine tumors of the sinonasal tract (9 of which were neuroendocrine carcinoma) treated with surgery (6 cases), neoadjuvant chemotherapy, and high-dose precision radiotherapy. In conclusion, small cell undifferentiated (neuroendocrine) carcinoma is an uncommon aggressive neoplasm where early diagnosis and local control may be important for improved prognosis. These patients frequently present with facial pain, swelling, and epistaxis. Visual disturbances are also common. The current report is the first to document a pattern of tumor presentation that was clinically interpreted to indicate odontogenic infection, resulting initially in patient management directed toward that presumed etiology. A thorough clinical examination of the teeth for discoloration, gross caries, extensive restorations, mobility, tenderness to percussion, pulp vitality testing, and radiographs to disclose any periapical radiolucent change is useful in determining whether local symptoms are likely of dental origin. Small cell carcinoma originating in the paranasal sinuses shows poor response to neoadjuvant chemotherapy, unlike small cell carcinoma primary to other sites including the lung. Though combined treatment achieved locoregional control, our patient quickly developed disseminated disease and died. REFERENCES 1. Raychowdhuri RN. Oat cell carcinoma and paranasal sinuses. J Laryngol & Otology 1965;79:253-5. 2. Koss LG, Spiro RH, Hajdu S. Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 1972;30:737-41. 3. Kameya T, Shimasato Y, Adachi I, Abe K, Ebihara S, Ono S. Neuroendocrine carcinoma of the paranasal sinus: a morphological and endocrinological study. Cancer 1980;45:330-9. 4. Rejowski JE, Campanella RS, Block LJ. Small cell carcinoma of the nose and paranasal sinuses. Otolaryngol Head Neck Surg 1982;90:516-7. 5. Silva EG, Butler JJ, Mackay B, Goepfert H. Neuroblastoma and neuroendocrine carcinomas of the nasal cavity. A proposed new classification. Cancer 1982;50:2388-405. 6. Perez-Ordonez B, Caruana SM, Huvos G, Shah JP. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum Pathol 1998;29:826-32. 7. Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer 1997;79:1729-36. 8. Fitzek MM, Thorton AF, Varvares M, Ancukiewicz M, Mcintyre J, Adams J, et al. Neuroendocrine tumours of the sinonasal tract. Cancer 2002;94:2623-34.

9. Mineta H, Miura K, Takebayashi S, Araki K, Ueda Y, Harada H, et al. Immunohistochemical analysis of small cell carcinoma of the head and neck: a report of four patients and a review of sixteen patients in the literature with ectopic hormone production. Ann Otol Rhinol Laryngol 2001;110:76-82. 10. Weiss MD, Defies HO, Taxy JB, Braine H. Primary small cell carcinoma of the paranasal sinuses. Arch Otolaryngol 1983;109: 341-3. 11. Soussi AC, Benghiat A, Holgate CS, Majumdar B. Neuro-endocrine tumours of the head and neck. J Laryngol & Otology 1990; 104:504-7. 12. Baugh RF, Wolf GT, McClatchey KD. Small cell carcinoma of the head and neck. Head & Neck 1986;8:343-54. 13. Pierce ST, Cibull ML, Metcalfe MS, Sloan D. Bone marrow metastases from small cell cancer of the head and neck. Head & Neck 1994;16:266-71. 14. Lo Re G, Vanzonieri V, Veronesi A, Dal Bo V, Barzan L, Zancanaro C, et al. Extrapulmonary small cell carcinoma: a single-institution experience and review of the literature. Ann Oncol 1994;5:909-13. 15. Noguchi K, Urade M, Sakuarai K, Nishimura N, Hasitani S, Kishimoto H. Small cell neuroendocrine carcinoma of the maxillary sinus—a case report and nude mouse transplantable model. Head & Neck 2002;24:491-6. 16. Pearse AGE. The cytochemistry and ultrastructure of polypeptide hormone producing cells of the APUD series and the embryologic, physiologic and pathologic implications of this concept. J Histochem Cytochem 1968;17:303-13. 17. Langley K. The neuroendocrine concept today. Ann N Y Acad Sci 1994;733:1-17. 18. DeLellis RA. The neuroendocrine system and its tumours. An overview. Am J Clin Pathol 2001;115(Suppl 1):S5-16. 19. Oberndorfer S. Karzinoide Tumoren des Dunndarms. Frankf Z Pathol 1907;1:426-32. 20. WHO. The World Health Organization histological typing of lung tumours. Am J Clin Pathol 1982;77:123-36. 21. Mills SE, Gaffey MJ, Frierson HF Jr. Atlas of tumour pathology: tumours of the upper aerodigestive tract and ear. 3rd ed. Washington, DC: Armed Forces Institute of Pathology; 2000. p. 179-80. 22. Gould VE, Linnoila I, Memoli VA, Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias and neoplasms. Lab Invest 1983;49:519-37. 23. Hoefler H, Denk H, Lackinger E, Helleis G, Polack JM, Heitz PU. Immunocytochemical demonstration of intermediate filament cytoskeleton proteins in human endocrine tissues and (neuro-) endocrine tumours. Virchows Arch A Pathol Anat Histopathol 1986;409:609-26. Reprint requests: Anastasia Georgiou, BDS, MDSc, FRACDS Department of Oral Pathology University of Sydney Westmead Hospital Westmead, New South Wales 2145 Australia [email protected]